Diabetes mellitus (DM) is a global health problem. The prevalence of diagnosed and undiagnosed diabetes in the US is progressively increasing from 7.8% in 2007, 14.5% in 2010 and expected to rise between 24.7% to 32.8% in 2050. Diabetes is the most common cause of end stage renal disease, responsible for more than 40% of all cases in the US, and this number are likely to continue to increase unabated. Endothelial cell dysfunction is a central pathophysiological mechanism that contributes to diabetes and diabetic nephropathy (DN). Dramatic alterations in arginine metabolism occur in endothelial injury due to changes in the activity and/or expression of nitric oxide synthases (NOS) and arginases. Arginase-2 is constitutively expressed and also inducible in endothelial cells as well as in kidney cells and, when elevated, can inhibit NOS activity/expression and induce endothelial NOS uncoupling, thus reducing NO bioavailability and inhibiting the NO/cGMP pathway. We hypothesize that arginases promote the development and progression of diabetic kidney damage. Aim 1: Test the hypothesis that arginase inhibition will be effective in the primary and secondary prevention of DN. Aim 2: Test the hypothesis that reduction in plasma arginine bioavailability contributes to the development and progression of DN. Aim 3: Test the hypothesis that elevated arginase-2 in endothelial cells contributes to tissue damage in DN. Our experimental approach will use both whole animals (Ins2Akita mice and their wild type (WT) littermates, Zucker diabetic fatty rats), genetically altered mice (mice with complete absence of arginase-2 expression (Arg2-/-), and transgenic mice that overexpress arginase-2 specifically in endothelial cells (Tie2Arg2) and cultured cells (glomerular microvascular endothelial cells (GMVEC) and endothelial cells that overexpress arginase-2) to fully define the role of arginases in DN. An understanding of the interaction between diabetes and arginases may help to elucidate mechanisms involved in diabetic renal disease and lead to the development of new therapeutic strategies to manage the disease process. PUBLIC HEALTH RELEVANCE: Currently, the only effective approaches to reduce the progression of diabetic nephropathy are to control the blood glucose levels and blood pressure. Attenuating the deleterious effects of arginases and/or kidney arginase-2 using arginase inhibitors will provide a new therapeutic approach to the treatment of diabetic nephropathy. Therefore, results of these studies will provide a basis for the development of new therapeutic modalities in the development and progression of diabetic nephropathy.